A few caveats - it's a mouse study, and even worse, part of it is just a mouse cell study. But it has some interesting bits and is worth a close look.

The authors begin by reviewing the current thinking about the cause of Alzheimer's (amyloid beta plaques, neuronal death, slow progression, etc. etc.) and the current treatments (several FDA approved acetylcholinesterase inhibitors, oh by the way they don't work very well and are not a cure). Then they go on to talk about the real cause of Alzheimer's (inflammation and crappy energetics - leading to cell death, slow progression, etc. etc.) and mention a funny little compound that might help with that, phytic acid.

Whoa. All the paleo peeps just squealed. PHYTIC ACID??? FROM WHOLE GRAINS??? Yes, that phytic acid. The one that binds all your minerals and leaves you anxious, insulin resistant, and fat. One of the reasons you don't eat oatmeal anymore. (via Dr. BG) Yes, phytic acid, why Stephan Guyenet has mysterious rice soaking in his fridge. (Honestly, I think traditionally prepared grains could be healthy enough if you are desperate, but they don't taste as good as meat and it takes so much effort… and I do worry about folks who are relatively sedentary or immobile and need the most nutrient-rich calories available.)

I actually wrote a bit about therapeutic uses of phytic acid before, but I was pretty sneaky, in my post on inositol.

So here's the scoop about phytic acid. Turns out that many nutrients and even anti-nutrients have multiple effects. I know. Shocking. I will quote the paper as they do a good job of writing here:

In this study, we investigated a novel protective treatment for AD pathology with phytic acid (PA, inositol hexakisphosphate). PA is structurally a myo-inositol sugar ring attached to 6 phosphate molecules. It is found naturally and ubiquitously, as a phosphate-storage phytochemical in unprocessed whole food grains, vegetables, and fruits, and as a key signaling molecule in mammalian cells. The Ca/Mg form of PA found in most plants is known as "Phytin" with its salt form known as "Phytate." Although PA is often described as a metal chelator, growing literature indicates that PA influences multiple processes, including antioxidant functions, anti-apoptotic effects, clathrin-coated endocytosis, DNA repair, and mRNA export from the nucleus. Phytic acid also lowers serum cholesterol and triglycerides. These studies suggest that PA possesses much broader functions than simply the originally-presumed metal binding properties

So what the authors suggest is that phytic acid is one of the many things (such as ketosis, calorie restriction, etc.) that can promote clean, happy, humming mitochondria. Happy mitochondria are one of my favorite things here at Evolutionary Psychiatry.

To get more detailed, there are many things that are postulated to increase SIRT1 (which is a class III histone and has epigenetic effects). High SIRT1 levels are found in long-lived yeast, flies, worms, and mice, and levels of SIRT1 are lower in folks with dementia. Calorie restriction and Red Wine Magic Food Resveratrol increase SIRT1 in animal models. The end result of increased SIRT1 seems to be increased autophagy. An awesome, dedicated clean-up crew keeping your neurons sparkly, as it were. Will phytic acid do the same for the brain as calorie restriction or resveratrol?

Well, in mouse cells, application of phytic acid seemed to do all the right things, increasing the expression of SIRT1 and other autophagy-promoting biochemical stuff. And, in Alzheimer's model mice given phytic acid-laced drinking water for six months, levels of SIRT1 increased, amyloid beta accumulation decreased, and other indicators of decreased oxidative stress and more efficient mitochondrial function were evident compared to control mice. AND brain levels of copper, zinc, and iron were no different between the control and phytic-acid mice.

(I'm wondering if any of that had to do with increasing the efficiency of second messengers, as inositol is thought to do, as I described in my previous post linked above).

So, the take home message is to eat whole grains to prevent Alzheimer's. Haha. Just kidding. Actually, the take home message is that nutrition and biochemistry are really complex. A molecule that has some downsides may also have some positives. Phytic acid seemed like the least noxious part of the chemical warfare that grains (and nuts and fruits and other plants) play. Since I don't pretend to have complete knowledge of the chemistry of the human brain, I like the evolutionary fallback position of an ancestral health lifestyle. Forget novel industrial foods created by a chemical company, and I won't be going to cute supplements (outside of the basic minerals and sunshine) unless I'm desperate.

Have a great Labor Day Weekend, everyone!

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Just want to add on a bit to address Rudolf's very astute comment (the eighth comment, below): : Isn't there another confounder, namely that rats, mice etc express phytase, and we don't?

Rudolph is saying that mice are better adapted to eating grains and have the enzyme phytase in their guts, which will cut up phytate into its components (inositol and a bunch of phosphate molecules). The authors do address this issue (sort of, though they don't make it that clear that humans do not metabolize phytic acid) - here's another paragraph from the paper - I'm a little irritated they didn't measure the phytic acid levels in the mouse brains when they had them, though:

It is important to emphasize that the effects of PA demonstrated here are distinct from those that have been attributed to its “backbone” and metabolite, inositol. Stereoisomers of myo-inositol (the non-phosphorylated backbone of PA) inhibit Aβ fibril assembly and protect neurons from Aβ-induced cytotoxicityin vitro. The stereoisomer scyllo-inositol inhibits Aβ aggregation, reduces soluble and insoluble Aβ, reduces plaque size and inhibits cognitive defects in a transgenic model of AD. Scyllo-inositol (ELND005) has been tested in animals and has entered phase 3 clinical trials for AD by Elan Corporation, plc. Recently, however, it had been shown to cause severe adverse drug effects in humans in two arms at doses 1 and 2 gram twice a day leading to death of 9 patients and discontinuation of both arms of this clinical trial. Interestingly, 6–7.4 g/day of phytic acid administered to patients did not have any adverse drug effects for up to 24 months. Our study indicates that phytic acid works by independent mechanisms. Additional support for the hypothesis that phytic acid may have effects beyond those of inositol come from studies showing elevated brain levels of phytic acid in rats fed a high phytate diet, indicating that some unmetabolized phytic acid is delivered to the brain, in addition to other species of phosphorylated inositols.

So - it's not all the inositol or other metabolized products from a mouse consuming phytic acid (which is synonymous with phytate, by the way). Phytate itself gets through in the mice, and, it seems, the question in humans (who shouldn't absorb much phytate at all - the phytate gets pooped out with the minerals, remember), is whether administration of phytate orally would make a difference in the brain. One interesting note in the paper is that the regular mouse diet had NO phytate, and the experimental diet was 2% phytate, and a diet rich in legumes, grains, and seeds would be about 5-6% phytate. The authors postulate that we humans in the developed world would be fine (hahaha quite an assumption given what is known about mineral consumption in epidemiologic studies in the developed world!) but that those in third world countries with marginal food consumption ought not to eat so much phytate…

It is something to consider to be studied as an injectable, if one has Alzheimer's. (Do not try this at home - in the quote above you will note that 9 people died taking scyllo-inositol in the clinical trials of that drug for dementia).

A "paleo" diet in humans will have its share of phytic acid (likely not the 5-6% of calories, though, I would imagine), especially if you don't soak all your nuts (I don't - I don't eat that many nuts and don't have the time or the space to mess with them - just like grains). See Melissa McEwen's latest post for more information.

If it's all the same to you, I think I'd rather activate Sirt1 with some good old fashioned red wine rather than some soaked grains, but hey, whatever floats peoples' boats! Shhh- don't remind me that the concentrations they usually use for resveratrol studies are usually only acquirable if you drink a whole vineyard's worth of wine... I'm up for a challenge!

I know of some upcoming research on phytic acid from colleagues of mine that is extremely exciting. Non-diet related but in oncology realm. The backstory is even more interesting. Another, context related chemical/nutrient case. In the right context does not always have to be that boogeyman.

Very interesting. One of my main concerns with trying out the new soylent drink (although I really really want to) is that it's made largely from oats. I have a problem with the idea of extreme oat consumption and the guys there don't really seem to properly address the issue).

Also, they're now saying that they're changing the ingredients to add brown rice flour to the formula for a better "mouth feel". I avoid taking brown rice too much because it's an anti-nutrient and I don't fully trust whole grains.

They're just like the food manufacturers that always have to bloody add shit to something that would be perfectly fine without it!

As an aside, I found your blog COMPLETELY by accident. I'm normally too lazy to read big articles like this. The music suggestion at the start of the article made me inextricably happy and unable to leave though. Not sure whether it was what you were listening to when writing or just a general music suggestion. It just made me smile a lot.

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About Me

Emily Deans, M.D.: I'm a psychiatrist in Massachusetts searching for evolutionary solutions to the general and mental health problems of the 21st century. Disclaimer: This information is for educational purposes only, and is in no way intended to be personal medical advice. Please ask your physician about any health guidelines seen in this blog, as everyone is different in his or her medical needs.